In spite of their usefulness as analgesics, opioids, such as morphine and heroin, have serious side effects such as euphoria, respiratory depression or constipation. Further, treatment regimens incorporating multiple dosages of opioid compounds risk patient addiction to those drugs. Thus, there has been a long-felt need to provide analgesic compounds without those side effects.
A considerable number of pharmacological and biochemical studies have been carried out in order to identify opioid receptors and their endogenous ligands to prepare peptide and non-peptide opioid ligands for the receptors. In the recent past, amino acid sequences of mu- (μ-), delta (δ-) and kappa (κ-) opioid receptor subtypes have been identified and reported. A further receptor subtype the ORL1-receptor has been identified and termed ORL1-receptor, and the isolation and structure of its endogenous agonist have been reported (Meunier, J.-C et al., Nature, Vol. 377, pp. 532-535 (1995)). The agonist compounds for ORL1-receptor are suggested to be effective in treating neurogenic inflammation (Tips, Vol. 18, pp. 293-300 (1997)), and to be potent analgesics with fewer psychological side effects and risk of patient addiction (D. Julius, Nature, Vol. 377, p. 476 (1995)).
WO 00/08013 discloses 2-substituted benzimodazole compounds as ORL1-agonists.